Clinical Trials /

A Study of Tivozanib in Combination With Durvalumab in Subjects With Untreated Advanced Hepatocellular Carcinoma

NCT03970616

Description:

This study will evaluate the safety, tolerability, DLTs, MTD, and preliminary anti tumor activity of tivozanib in combination with durvalumab in subjects with advanced HCC.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Tivozanib in Combination With Durvalumab in Subjects With Untreated Advanced Hepatocellular Carcinoma
  • Official Title: A Phase 1b/2, Open-Label, Study of Tivozanib in Combination With Durvalumab in Subjects With Untreated Advanced Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: AV-951-18-121
  • NCT ID: NCT03970616

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
TivozanibFotivdaTivozanib in Combination with Durvalumab
DurvalumabImfinziTivozanib in Combination with Durvalumab

Purpose

This study will evaluate the safety, tolerability, DLTs, MTD, and preliminary anti tumor activity of tivozanib in combination with durvalumab in subjects with advanced HCC.

Trial Arms

NameTypeDescriptionInterventions
Tivozanib in Combination with DurvalumabExperimentalTivozanib in Combination with Durvalumab
  • Tivozanib
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          1. ≥ 18 years old

          2. Signed and dated written informed consent

          3. Untreated histologically or cytologically confirmed metastatic hepatocellular
             carcinoma. Measurable or evaluable disease by RECIST 1.1 criteria.

          4. Child-Pugh Class A.

          5. ECOG performance status ≤ 1 and life expectancy ≥ 3 months.

          6. Body weight > 30 kg

          7. Measured creatinine clearance (crCL) >40 mL/min or calculated crCL >40 mL/min as
             determined by Cockcroft-Gault (using actual body weight) Males CrCL = Weight (kg) ×
             (140 - Age) 72 × serum creatinine (mg/dL) Females CrCL = Weight (kg) × (140 - Age) 85
             × serum creatinine (mg/dL)

          8. Sexually active pre-menopausal female subjects (and female partners of male subjects)
             must use highly effective contraceptive measures, while on study and for at least 90
             days after the last dose of study drug. Sexually active male subjects must use
             adequate contraceptive measures, while on study and for at least 90 days after the
             last dose of study drug. All fertile male and female subjects and their partners must
             agree to use a highly effective method of contraception.

        Exclusion Criteria:

          1. Subjects who have received prior systemic treatment for HCC

          2. Female subjects who are pregnant or breastfeeding or male or female subjects of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of study drug.

          3. Brain metastases or spinal cord compression. Subjects with suspected brain metastases
             at screening should have an MRI (preferred) or CT scan each preferable with IV
             contrast of the brain prior to study entry. Brain metastases will not be recorded on
             RECIST Target Lesions at baseline.

          4. Any of the following hematologic abnormalities:

               -  Hemoglobin < 9.0 g/dL

               -  Absolute neutrophil count (ANC) < 1500 per mm3

               -  Platelet count < 100,000 per mm3

          5. Any of the following serum chemistry abnormalities:

               -  Total bilirubin > 2 × ULN (>2.5 mg/dL in subjects with Gilbert's syndrome)

               -  AST or ALT > 5 × ULN

               -  Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone
                  metastasis)

               -  Serum creatinine > 1.5 × ULN

               -  > 2+ proteinuria

               -  Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with
                  the exception of alopecia, vitiligo, and the laboratory values defined in the
                  inclusion criteria:

                    -  Subjects with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis
                       after consultation with the Medical Monitor

                    -  Subjects with irreversible toxicity not reasonably expected to be
                       exacerbated by treatment with durvalumab may be included only after
                       consultation with the Medical Monitor

          6. History of hepatic encephalopathy within past 12 months or requirement for medications
             to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if used for
             purposes of hepatic encephalopathy).

          7. GI Bleeding (eg, esophageal varices or ulcer bleeding) within 12 months. (Note: For
             patients with a history of GI bleeding for more than 12 months or assessed as high
             risk for esophageal variceal by the Investigator, adequate endoscopic therapy
             according to institutional standards is required).

          8. Clinically meaningful ascites defined as ascites requiring non-pharmacologic
             intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior
             to the first scheduled dose. Subjects on stable doses of diuretics for ascites for ≥ 2
             months are eligible.

          9. Main portal vein thrombosis (Vp4) as documented on imaging. (VP4 is defined as portal
             vein thrombosis in the main trunk of the portal vein or a portal vein branch
             contralateral to the primarily involved lobe (or both).

         10. For subjects who require ongoing therapeutic anti-coagulation or anti-platelet
             therapy; the subject must be off either therapy for at least 7 days prior to the first
             dose of investigational product. Low-dose aspirin for cardiac prophylaxis/protection
             is permitted per local institutional standards.

         11. Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus
             (HDV). HBV positive [presence of hepatitis B surface antigen (HBsAg) and/or hepatitis
             B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10IU/ml)]; HCV positive
             (presence of anti-HCV antibodies); HDV positive (presence of anti-HDV antibodies).

         12. Major surgery (as defined by the investigator) within 28 days prior to first dose of
             IP or still recovering from prior surgery. Local procedures (eg, core needle biopsy,
             and prostate biopsy) are allowed if completed at least 3 days prior to the
             administration of the first dose of study treatment.

         13. Significant cardiovascular disease, including:

               -  Clinically symptomatic heart failure. Subjects with a history of heart failure
                  must have an ECHO or MUGA scan to document left ventricular ejection fraction
                  (LVEF) > 45% prior to start of protocol therapy

               -  Any New York Heart Association classification ≥ Class 2 (prefer Class 0 or 1)

               -  Any stenting procedure within the last 3 months

               -  Venous thromboembolism or arterial thromboembolism within the last 3 months

               -  Any IVC tumor thrombosis

               -  History of a hemorrhagic event (i.e., GI bleed within 6 months)

               -  Uncontrolled hypertension: blood pressure >150/95 mmHg on more than 2
                  antihypertensive medications, on two consecutive measurements obtained at least
                  24 hours apart. Subjects with a history of hypertension must have been on stable
                  doses of anti-hypertensive drugs for ≥ 2 weeks prior to start of protocol
                  therapy.

               -  Myocardial infarction within 3 months prior to start of protocol therapy

         14. Subjects with delayed healing of wounds, ulcers, and/or bone fractures

         15. Serious/active infection or infection requiring parenteral antibiotics

         16. Inadequate recovery from any prior surgical procedure; major surgical procedure within
             4 weeks prior to start of protocol therapy.

         17. Inability to comply with protocol requirements

         18. History of another primary malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease ≥ 5
                  years before the first dose of study drug and low potential risk for recurrence

               -  Adequately treated non-melanoma skin cancer of lentigo maligna without evidence
                  of disease

         19. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis testing in
             line with local practice), , hepatitis C, or human immunodeficiency virus (positive
             HIV 1/2 antibodies). Subjects positive for hepatitis C (HCV) antibody are eligible
             only if polymerase chain reaction is negative for HCV RNA.

         20. Patients with a history or current HBV infection (detectable HBV DNA), should be
             placed on anti-viral treatment and tested at every cycle for HBV DNA viral load.

         21. Treatment with systemic hormonal therapy within 3 weeks prior to start of protocol
             therapy, with the exception of:

               -  Hormonal therapy for appetite stimulation or contraception

               -  Nasal, ophthalmic, inhaled and topical steroid preparations

               -  Oral replacement therapy for adrenal insufficiency

               -  Low-dose maintenance steroid therapy (equivalent of prednisone 10mg/day) for
                  other conditions

               -  Hormone replacement therapy

         22. Strong CYP3A4 inhibitors or inducers within 2 weeks prior to start of, or during,
             protocol therapy.

         23. Prior exposure to tivozanib or any checkpoint inhibitor

         24. History of allogeneic organ transplantation

         25. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
             criterion:

               -  Subjects with vitiligo or alopecia

               -  Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Subjects without active disease in the last 5 years may be included but only
                  after consultation with Medical Monitor

               -  Subjects with celiac disease controlled by diet alone

         26. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease,
             serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric
             illness/social situations that would limit compliance with study requirement,
             substantially increase risk of incurring AEs or compromise the ability of the subject
             to give written informed consent

         27. History of leptomeningeal carcinomatosis

         28. History of active primary immunodeficiency

         29. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
             calculated from 3 ECGs (within 15 minutes at 5 minutes apart

         30. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients

         31. Concurrent enrolment in another clinical study, unless it is an observational (non
             interventional) clinical study or during the follow-up period of an interventional
             study

         32. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
             drug. Note: Subjects, if enrolled, should not receive live vaccine whilst receiving
             study drug and up to 30 days after the last dose of study drug.

         33. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

         34. Previous study drug assignment in the present study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment Emergent Adverse Events (TEAEs)
Time Frame:Approximately 24 months; Through study completion
Safety Issue:
Description:To establish the safety of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma (HCC).

Secondary Outcome Measures

Measure:Response Rate (Objective Response Rate)
Time Frame:Approximately 24 months
Safety Issue:
Description:To estimate the response rate of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
Measure:Progression Free Survival (PFS)
Time Frame:Approximately 24 months
Safety Issue:
Description:To estimate the progression free survival (PFS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
Measure:Overall Survival (OS)
Time Frame:Approximately 24 months; Through study completion
Safety Issue:
Description:To estimate the overall survival (OS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AVEO Pharmaceuticals, Inc.

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